Triclosan and silver compound containing medical devices

ABSTRACT

The present invention relates to polymeric medical articles comprising combinations of triclosan and silver-containing compounds. It is based, at least in part, on the discovery that these agents act synergistically, thereby permitting the use of relatively low levels of both agents. While it had been previously found that triclosan can be particularly useful when used in conjunction with chlorhexidine, it has been further discovered that medical articles having suitable antimicrobial properties may be prepared, according to the present invention, which contain triclosan without chlorhexidine. Such medical articles offer the advantage of preventing or inhibiting infection while avoiding undesirable adverse reactions to chlorhexidine by individuals that may have sensitivity to chlorhexidine.

1.0 INTRODUCTION

[0001] The present invention relates to medical devices comprisingsynergistic combinations of triclosan and silver containing compounds.

2.0 BACKGROUND OF THE INVENTION

[0002] Whenever a medical device comes in contact with a patient, a riskof infection is created. Thus, a contaminated examination glove, tonguedepressor, or stethoscope could transmit infection. The risk ofinfection dramatically increases for invasive medical devices, such asintravenous catheters, arterial grafts, intrathecal or intracerebralshunts and prosthetic devices, which not only are, themselves, inintimate contact with body tissues and fluids, but also create a portalof entry for pathogens.

[0003] A number of methods for reducing the risk of infection have beendeveloped which incorporate anti-infective agents into medical devices,none of which have been clinically proven to be completely satisfactory.Such devices desirably provide effective levels of anti-infective agentduring the entire period that the device is being used. This sustainedrelease may be problematic to achieve, in that a mechanism fordispersing anti-infective agent over a prolonged period of time may berequired, and the incorporation of sufficient amounts of anti-infectiveagent may adversely affect the surface characteristics of the device.The difficulties encountered in providing effective antimicrobialprotection increase with the development of drug-resistant pathogens.

[0004] One potential solution to these problems is the use of asynergistic combination of anti-infective agents that requiresrelatively low concentrations of individual anti-infective agents whichmay have differing patterns of bioavailability.

[0005] Two well-known anti-infective agents are chlorhexidine andtriclosan. The following patents and patent application relate to theuse of chlorhexidine and/or triclosan in medical devices.

[0006] U.S. Pat. No. 4,723,950 by Lee relates to a microbicidal tubewhich may be incorporated into the outlet tube of a urine drainage bag.The microbicidal tube is manufactured from polymeric materials capableof absorbing and releasing anti-microbial substances in a controllablesustained time release mechanism, activated upon contact with dropletsof urine, thereby preventing the retrograde migration of infectiousorganisms into the drainage bag. The microbicidal tube may be producedby one of three processes: (1) a porous material, such as polypropylene,is impregnated with at least one microbicidal agent, and then coatedwith a hydrophilic polymer which swells upon contact with urine, causingthe leaching out of the microbicidal agent; (2) a porous material, suchas high density polyethylene, is impregnated with a hydrophilic polymerand at least one microbicidal agent; and (3) a polymer, such assilicone, is compounded and co-extruded with at least one microbicidalagent, and then coated with a hydrophilic polymer. A broad range ofmicrobicidal agents are disclosed, including chlorhexidine andtriclosan, and combinations thereof. The purpose of Lee's device is toallow the leaching out of microbicidal agents into urine contained inthe drainage bag; similar leaching of microbicidal agents into thebloodstream of a patient may be undesirable.

[0007] U.S. Pat. No. 5,091,442 by Milner relates to tubular articles,such as condoms and catheters, which are rendered antimicrobiallyeffective by the incorporation of a non-ionic sparingly solubleantimicrobial agent, such as triclosan. The tubular articles are made ofmaterials which include natural rubber, polyvinyl chloride andpolyurethane. Antimicrobial agent may be distributed throughout thearticle, or in a coating thereon. A condom prepared from natural rubberlatex containing 1% by weight of triclosan, then dipped in an aqueoussolution of chlorhexidine, is disclosed. U.S. Pat. Nos. 5,180,605 and5,261,421, both by Milner, relate to similar technology applied togloves.

[0008] U.S. Pat. Nos. 5,033,488 and 5,209,251, both by Curtis et al.,relate to dental floss prepared from expanded polytetrafluoroethylene(PTFE) and coated with microcrystalline wax. Antimicrobial agents suchas chlorhexidine or triclosan may be incorporated into the coated floss.

[0009] U.S. Pat. No. 5,200,194 by Edgren et al. relates to an oralosmotic device comprising a thin semipermeable membrane wall surroundinga compartment housing a “beneficial agent” (that is at least somewhatsoluble in saliva) and a fibrous support material composed ofhydrophilic water-insoluble fibers. The patent lists a wide variety of“beneficial agents” which may be incorporated into the oral osmoticdevice, including chlorhexidine and triclosan.

[0010] U.S. Pat. No. 5,019,096 by Fox, Jr., et al. relates toinfection-resistant medical devices comprising a synergistic combinationof a silver compound (such as silver sulfadiazine) and chlorhexidine.

[0011] International Patent Application No. PCT/GB92/01481, PublicationNo. WO 93/02717, relates to an adhesive product comprising residues of acopolymerisable emulsifier comprising a medicament, which may bepovidone iodine, triclosan, or chlorhexidine.

[0012] International Patent Application No. PCT/US96/20932, PublicationNo. WO 97/25085, relates to polymeric medical articles comprisingsynergistic combinations of chlorhexidine and triclosan which utilizerelatively low levels of these agents.

[0013] In contrast to the present invention, none of the above-citedreferences teach medical articles comprising synergistic combinations oftriclosan and silver compounds which utilize relatively low levels ofthese agents and provide effective levels of antimicrobial activity,even in the absence of chlorhexidine.

3.0 SUMMARY OF THE INVENTION

[0014] The present invention relates to polymeric medical articlescomprising combinations of triclosan and/or other chlorinated phenolsand silver-containing compounds. It is based, at least in part, on thediscovery that these agents act synergistically, thereby permitting theuse of relatively low levels of both agents. While it had beenpreviously found that triclosan can be particularly useful when used inconjunction with chlorhexidine, it has been further discovered thatmedical articles having suitable antimicrobial properties may beprepared, according to the present invention, which contain triclosanand a silver compound without chlorhexidine. Such medical articles offerthe advantage of preventing or inhibiting infection while avoidingundesirable adverse reactions to chlorhexidine by individuals that mayhave a sensitivity to chlorhexidine, such as a chlorhexidine allergy.

[0015] The present invention is also based, at least in part, on thediscovery that the surface of medical articles, especially catheters,impregnated with triclosan and silver compounds generally were found tobe smoother and shinier in comparison with catheters impregnated withtriclosan and chlorhexidine. Even when the triclosan-silver compoundimpregnated catheters exhibited commensurate or smaller zones ofinhibition compared to triclosan-chlorhexidine catheters, there waslittle or no bacterial adherence observed on the former when exposed tobacterial culture. Microbial adherence on the surfaces of medicaldevices are the result of a deposition of fibrinogen and fibronectin onthe surface which forms a host biofilm. Because bacteria tend to adhereto this biofilm, glycocalyx forms which serves as a bacterial reservoircausing blood stream infections. Without being bound by any particulartheory, it is believed that medical articles of the invention, by virtueof their smooth surfaces, may be less physically irritating than priorart devices, may be less likely to provoke fibrinogen and/or fibronectindeposition, and therefore may avoid bacterial colonization.

4.0 DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention relates to medical articles comprisingcombinations of triclosan and/or another chlorinated phenol and one ormore silver-containing compound (hereafter, “silver compound”).

[0017] While not being bound or limited by any particular theory, it isbelieved that the combination of triclosan and a silver compound forms asoluble complex. This would explain observations, such as those setforth in Example Section 5 below, that the presence of triclosanimproves the solubility of various silver compounds, thereby improvingtheir bioavailability.

[0018] As shown in Example Sections 7, 9-17 and 19, medical articles,which may be hydrophilic or hydrophobic, treated with combinations oftriclosan and various silver compounds exhibit desirable antimicrobialproperties. As shown in Example Sections 8, 13 and 14 such articlesexhibit smooth surfaces that tend to resist bacterial adherence, whichmay be at least partly responsible for their antimicrobial quality.

[0019] The present invention provides for medical articles treated withchlorinated phenols other than triclosan in combination with one or moresilver compound. As shown in Example Section 18, such combinationsresult in enhanced antimicrobial activity. Suitable chlorinated phenolsinclude parachlorometaxylenol (“PCMX”) and dichlorometaxylenol (“DCMX”).The amount of chlorinated phenol which may be used is as set forth belowfor triclosan, but may be adjusted for differences in potency whentested against a particular microbe. For example, in specific,non-limiting embodiments of the invention polymeric medical articles maybe prepared using treatment solutions comprising between about 0.1 and 5percent, preferably between about 0.3 and 1.5 percent, of a silvercompound, and between about 0.1 and 20 percent, preferably between about0.1 and 8 percent, of a chlorinated phenol, preferably PCMX. The presentinvention also provides for medical articles comprising triclosan inaddition to another chlorinated phenol.

[0020] In additional embodiments, the present invention provides formedical articles having anti-infective activity which comprise triclosanand/or another chlorinated phenol, a silver compound, and ananti-inflammatory agent. It has been found that the addition of ananti-inflammatory compound enhances the antimicrobial activity of suchdevices (see Section 17 below).

[0021] In still further embodiments, the present invention provides formedical articles which have been treated with a hydrogel, and furthercomprise a metal compound.

[0022] The term triclosan (“TC”), as used herein, refers to a compoundalso known as 2,4,4′-trichloro-2′-hydroxydiphenyl ether and also knownas 5-chloro-2-(2,4-dichlorophenoxy)phenol.

[0023] The term silver compound, as used herein, refers to a compoundcomprising silver, either in the form of a silver atom or a silver ionunlinked or linked to another molecule via a covalent or noncovalent(e.g., ionic) linkage, including but not limited to covalent compoundssuch as silver sulfadiazine (“AgSD”) and silver salts such as silveroxide (“Ag₂O”), silver carbonate (“Ag₂CO₃”), silver deoxycholate, silversalicylate, silver iodide, silver nitrate (“AgNO₃”), silverparaaminobenzoate, silver paraaminosalicylate, silver acetylsalicylate,silver ethylenediaminetetraacetic acid (“Ag EDTA”), silver picrate,silver protein, silver citrate, silver lactate and silver laurate.

[0024] The terms “medical article” and “medical device” are usedinterchangeably herein. Medical articles that may be treated accordingto the invention are either fabricated from or coated or treated withbiomedical polymer (and hence may be referred to as “polymer-containingmedical articles”) and include, but are not limited to, cathetersincluding urinary catheters and vascular catheters (e.g., peripheral andcentral vascular catheters), wound drainage tubes, arterial grafts, softtissue patches (such as polytetrafluoroethylene (“PTFE”) soft tissuepatches), gloves, shunts, stents, tracheal catheters, wound dressings,sutures, guide wires and prosthetic devices (e.g., heart valves andLVADs). Vascular catheters which may be prepared according to thepresent invention include, but are not limited to, single and multiplelumen central venous catheters, peripherally inserted central venouscatheters, emergency infusion catheters, percutaneous sheath introducersystems and thermodilution catheters, including the hubs and ports ofsuch vascular catheters. The present invention may be further applied tomedical articles that have been prepared according to U.S. Pat. No.5,019,096 by Fox, Jr. et al.

[0025] The following are descriptions of particular embodiments of theinvention.

[0026] Percentages recited herein refer to weight/volume (w/v), exceptas indicated otherwise.

[0027] The present invention provides, in various non-limitingembodiments, for: (1) treatment solutions comprising between about 0.1and 5 percent, and preferably between about 0.3 and 1.5 percent of asilver compound; and between about 0.1 and 20 percent and preferablybetween about 0.1 and 8 percent of triclosan and/or other chlorinatedphenol; (2) treatment solutions comprising between about 0.1 and 10percent, and preferably between about 1 and 5 percent of one or morehydrophilic or hydrophobic polymer; between about 0.1 and 5 percent, andpreferably between about 0.3 and 1.5 percent of a silver compound; andbetween about 0.1 and 20 percent, and preferably between about 0.1 and 8percent of triclosan and/or other chlorinated phenol; (3)polymer-containing medical articles treated with a treatment solution asset forth in (1) or (2) above, and articles physically equivalentthereto (that is to say, articles prepared by a different method buthaving essentially the same elements in the same proportions); (4)polymer-containing medical articles treated with treatment solutions setforth in (1) or (2) above wherein the articles are dried and thereaftercoated with an anti-infective and/or polymeric coating in accordancewith a two-step process. The treatment solutions set forth in (1) or (2)may optionally further comprise (i) an organic acid, at a concentrationof between about 0 and 5 percent, preferably between about 0.1 and 2percent; (ii) an anti-inflammatory agent, at a concentration of betweenabout 1 and 5 percent, preferably between about 0.1 and 1 percent; (iii)an antimicrobial other than a silver compound or triclosan at aconcentration of between about 0.1 and 10 percent; and/or (iv) ahydrogel at a concentration of between about 0.5 to 10 percent,preferably between about 1 and 5 percent. In preferred non-limitingembodiments of the invention, the amount of silver present as silveratom or silver ion is about 0.9%. In preferred non-limiting embodimentsof the invention, the treatment solution and/or medical article does notcontain chlorhexidine or a chlorhexidine salt. The medical articles are“treated” by exposing them, for an effective period of time, to thetreatment solution, where an “effective period of time” is that periodof time sufficient to introduce anti-infective quantities of triclosanand/or other chlorinated phenol and silver compound. Where theconcentration of gtriclosan and/or other chlorinated phenol in thetreatment solution is between 0.1 and 8 percent, the effective period oftime may be between about 30 seconds and one hour; where theconcentration of tricolsan and/or other chlorinated phenol in thetreatment solution is between about 9 and 20 percent, the effectiveperiod of time may be between about 10 seconds and 2 minutes. Longerperiods of exposure may be used provided that undesirable deteriorationof the medical article does not occur.

[0028] The term “about” indicates a variation within 20 percent.

[0029] In particular non-limiting embodiments of the invention, wherethe medical article is a vascular catheter, such as a central venouscatheter, the amount of triclosan contained is about 100-600 μg/cm,preferably about 400-500 μg/cm and the amount of silver atom or ion is25 to 100 μg/cm, preferably 30 to 80 μg/cm. The triclosan and silver arein releasable form, i.e., extractable by a solvent that does notsubstantially dissolve the catheter.

[0030] Medical articles prepared according to the invention may betreated on their external surface, internal surface, or both. Forexample, and not by way of limitation, where the medical article is acatheter, the internal surface and/or external surface of the cathetermay be treated according to the invention. For example, where it isdesired to treat both internal and external surfaces, an open-endedcatheter may be placed in a treatment solution such that the treatmentsolution fills the catheter lumen. If only the external surface is tocome in contact with treatment solution, the ends of the catheter may besealed before it is placed in the treatment solution. If only theinternal surface is to come in contact with treatment solution, thesolution may be allowed to pass through and fill the lumen but thecatheter is not immersed in the treatment solution.

[0031] Medical articles may be dipped, soaked, or otherwise have asurface coated. The term “dipped” suggests briefer exposure to treatmentsolution relative to soaking, and preferably is for a period of timeless than fifteen minutes.

[0032] Successful treatment of a medical article with a polymercomprising an anti-infective agent may be problematic, particularlywhere the medical article has a hydrophobic surface. The adherence ofthe polymer may depend upon (1) the polymeric matrix in which theanti-infective agent is suspended; (2) compatibility (or lack thereof)between the agent-polymeric matrix and the surface of the article; (3)the solvent system; and (4) the thickness of polymer/anti-infectiveagent desirably applied. Furthermore, the rates of release of variousanti-infective agents from diverse polymers may differ. To address theseissues, the present invention provides for two different methods fortreating medical articles: a one-step method, and a two-step method,both of which are set forth below.

[0033] Polymers, triclosan, and silver compounds used according to theinvention may be sparingly soluble in certain solvents or solventmixtures. It therefore may be desirable to first dissolve the relevantmaterial in a solvent or component of a solvent system which favorsdissolving. For example, where polyurethane, triclosan, and a silvercompound are desirably incorporated into an alcohol/tetrahydrofuran(“THF”) solvent system, the polyurethane may first be dissolved in THFand the triclosan and silver compound may be dissolved in alcohol (incertain instances with the addition of an aqueous solution of ammonia(referred to interchangeably herein as either ammonia, ammoniumhydroxide, or NH₃) to facilitate solubilization of the silver compound),before the THF and alcohol components are mixed. The use of a solventsystem comprising ammonia may be particularly desirable when a silversalt is used.

4.1 HYDROPHILIC ARTICLE TREATED WITH A SOLUTION OF A HYRDOPHILIC POLYMER

[0034] In one particular set of non-limiting embodiments, the presentinvention provides for a hydrophilic polymeric medical article (i.e., amedical article fabricated from a hydrophilic polymer) treated bycoating, dipping or soaking the article in a treatment solution of ahydrophilic polymer comprising a silver compound and triclosan (and/orother chlorinated phenol) wherein the silver compound and triclosan orother chlorinated phenol are present in amounts such that theircombination, in the treated article, has effective anti-microbialactivity. The term “effective antimicrobial activity” refers to anability to decrease the number of colony-forming units of a bacterium oryeast, in a 24 hour period, by a factor of ten or more and preferably afactor of 100 or more. The terms “treat”, “treated”, etc., as usedherein, refer to coating, impregnating, or coating and impregnating amedical article with anti-infective agent. The term “hydrophilicpolymer”, as used herein, refers to polymers which have a waterabsorption greater than 0.6 percent by weight (and, in preferredembodiments, less than 2 percent by weight; as measured by a 24 hourimmersion in distilled water, as described in ASTM Designation D570-81)including, but not limited to biomedical polyurethanes (e.g.,ether-based polyurethanes and ester-based polyurethanes, as set forth inBaker, 1987, in Controlled Release of Biologically Active Agents, JohnWiley and Sons, pp. 175-177 and Lelah and Cooper, 1986, Polyurethanes inMedicine, CRC Press, Inc., Florida pp. 57-67; polyurethanes comprisingsubstantially aliphatic backbones such as Tecoflex™ 93A; polyurethanescomprising substantially aromatic backbones such as Tecothane™; andPellethane™), polylactic acid, polyglycolic acid, natural rubber latex,and gauze or water-absorbent fabric, including cotton gauze and silksuture material. In specific, non-limiting embodiments, the hydrophilicmedical article is a polyurethane catheter which has been treated with(e.g., coated, dipped or soaked in) a treatment solution comprising (i)between about 0.1 and 10 percent, and preferably between about 1 and 5percent, of one or more biomedical polyurethane; (ii) between about 0.1and 5 percent, and preferably between 0.3 and 1.5 percent, of a silvercompound; and (iii) between about 0.1 and 20 percent, and preferablybetween about 0.1 and 8 percent, of triclosan and/or other chlorinatedphenol.

4.2 HYDROPHILIC ARTICLE TREATED WITH A SOLUTION OF A HYDROPHOBIC POLYMER

[0035] In another set of particular non-limiting embodiments, thepresent invention provides for a hydrophilic polymeric medical articletreated by coating, dipping or soaking the article in a treatmentsolution of a hydrophobic polymer comprising a silver compound andtriclosan (and/or other chlorinated phenol), wherein the silver compoundand triclosan and/or other chlorinated phenol are present in amountssuch that their combination, in the treated article, has effectiveanti-microbial activity. The term “hydrophobic polymer”, as used herein,refers to a polymer which has a water absorption of less than 0.6% andincludes, but is not limited to, silicone polymers such as biomedicalsilicones (e.g., Silastic Type A) or elastomers (e.g., as set forth inBaker, 1987, in Controlled Release of Biologically Active Agents, JohnWiley and Sons, pp. 156-162), Dacron, polytetrafluoroethylene (“PTFE”,also “Teflon”), polyvinyl chloride (“PVC”), cellulose acetate,polycarbonate, and copolymers such as silicone-polyurethane copolymers(e.g., PTUE 203 and PTUE 205 polyurethane-silicone interpenetratingpolymer). In one specific, non-limiting embodiment, the medical articleis a polyurethane catheter which has been dipped or soaked in atreatment solution comprising (i) between about 0.1 and 10 percent, andpreferably between about 1 and 5 percent, of a polyurethane-siliconecopolymer; (ii) between about 0.1 and 5 percent, and preferably betweenabout 0.3 and 1.5 percent, of a silver compound; and (iii) between about0.1 and 20 percent, and preferably between about 0.1 and 8 percent, oftriclosan and/or other chlorinated phenol.

4.3 HYDROPHOBIC ARTICLE TREATED WITH A SOLUTION OF A HYDROPHOBIC POLYMER

[0036] In another set of particular non-limiting embodiments, thepresent invention provides for a hydrophobic polymeric medical articletreated by coating, dipping or soaking the article in a treatmentsolution of hydrophobic polymer comprising a silver compound andtriclosan and/or other chlorinated phenol, wherein the silver compoundand triclosan and/or other chlorinated phenol are present in amountssuch that their combination, in the treated article, has effectiveantimicrobial activity. In one specific, non-limiting embodiment, themedical article is a silicone catheter or a polyvinylchloride catheterwhich has been dipped or soaked in a treatment solution comprising (i)between about 0.1 and 10 percent, and preferably between about 1 and 5percent, of a silicone polymer; (ii) between about 0.1 and 5 percent,and preferably between about 0.3 and 1.5 percent, of a silver compound;and (iii) between about 0.1 and percent, and preferably between about0.1 and 8 percent, of triclosan and/or other chlorinated phenol.

4.4 HYDROPHOBIC ARTICLE TREATED WITH A SOLUTION OF A HYDROPHILIC POLYMER

[0037] In yet another set of particular non-limiting embodiments, thepresent invention provides for a hydrophobic polymeric medical articletreated by coating, dipping or soaking the article in a treatmentsolution of hydrophilic polymer comprising a silver compound andtriclosan and/or other chlorinated phenol, wherein the silver compoundand triclosan and/or other chlorinated phenol are present in amountssuch that their combination, in the treated article, has effectiveanti-microbial activity. In a specific, non-limiting embodiment, themedical article is a silicone catheter or Teflon graft which has beendipped, coated or soaked in a treatment solution comprising (i) betweenabout 0.1 and 10 percent, and preferably between about I and 5 percent,of a biomedical polyurethane polymer; (ii) between about 0.1 and 5percent, and preferably between about 0.3 and 1.5 percent, of a silvercompound; and (iii) between about 0.1 and 20 percent, and preferablybetween about 0.1 and 8 percent, of triclosan and/or other chlorinatedphenol.

4.5 MEDICAL ARTICLES IMPREGNATED WITH TRICLOSAN AND A SILVER COMPOUND BYA ONE-STEP METHOD

[0038] According to the one-step method of the invention, a polymericmedical article may be treated with a solution comprising one or moresilver compounds, triclosan and/or other chlorinated phenol, andoptionally containing a biomedical polymer, dissolved in one or moresolvents, wherein the solvent(s) selected is (are) capable of swellingthe polymeric medical article to be treated; such a solution is referredto herein as an “impregnating solution” (which is a species of treatmentsolution), and the process by which the article is treated withtriclosan and a silver compound is referred to as “impregnation”.Suitable solvents include, but are not limited to, tetrahydrofuran(“THF”), dichloromethane, carbon tetrachloride, methanol, ethanol,methyl ethyl ketone, heptane, M-Pyrol and hexane, and mixtures thereof.The term “reagent alcohol” as used herein refers to a solutioncontaining essentially 5% v/v methanol, 5% v/v isopropanol, and 90% v/vethanol. The biomedical polymer may be hydrophilic or hydrophobic, andincludes the various polymers set forth above.

[0039] If a hydrophilic polymeric medical article is to be impregnatedwith a silver compound and triclosan and/or other chlorinated phenol,the impregnating solution may, in specific non-limiting embodiments,comprise the following (percentages of solvents in this paragraph beingvolume/volume (v/v) except where noted to be weight/volume (w/v)): 95%ethanol/5% water; 95% reagent alcohol/5% water; 70% ethanol/30% water;70% reagent alcohol/30% water; 50% ethanol/50% water; 50% reagentalcohol/50% water; 30% ethanol/70% THF; 30% reagent alcohol/70% THF; 30%methanol/70% THF; 10% ethanol/10% ammonia/80% THF; 10% reagentalcohol/10% ammonia/80% THF; 90% ethanol/10% THF; 90% reagentalcohol/10% THF; 90% methanol/10% THF; 100% ethanol or 100% reagentalcohol. The treatment solutions may comprise between about 0.1 and 10percent (w/v), and preferably between about 1 and 5 percent (w/v), ofone or more dissolved polymer (e.g., one or more species ofpolyurethane, silicone, or hydrogel). Preferred soaking times accordingto the one-step method vary between 15 seconds and 1 hour, dependingupon the polymer selected. A shorter soaking time in a drug/solventsystem is preferred since it is less likely to negatively affect thephysical integrity of the polymeric device, particularly polyurethanecatheters. In order to attain a sufficient drug uptake using a shortersoaking time, it is preferred that the amount of triclosan or otherchlorinated phenol in the treatment solution be between about 10 and 20percent (w/v). For a specific example of a method that uses higherlevels of triclosan and a shorter soaking time see Section 9 below.

[0040] If a hydrophobic polymeric medical article is to be impregnatedwith a silver compound and triclosan and/or other chlorinated phenol,the impregnating solution may, in specific non-limiting embodiments,comprise the following (percentages of solvents in this paragraph beingvolume/volume (v/v) except where noted to be weight/volume (w/v)): 10%methanol/90% THF; 10% ethanol/90% THF; 10% reagent alcohol/90% THF; 10%ethanol/10% ammonia/80% THF; 10% reagent alcohol/10% ammonia/80% THF;30% ethanol 70% THF; 30% reagent alcohol/70% THF; 30% methanol/70% THF;1-5 percent (w/v) silicone polymer in 10% methanol/90% THF; 1-5 percent(w/v) silicone polymer in 10% ethanol/90% THF; 1-5 percent (w/v)silicone polymer in 10% reagent alcohol/90% THF; 1-2 percent (w/v)polylactic acid in 10% methanol/90% THF; 1-2 percent w/v polylactic acidin 10% ethanol/90% THF; 1-2 percent (w/v) polylactic acid in 10% reagentalcohol/90% THF; 1-5 percent (w/v) silicone polymer in 30% methanol/70%THF; 1-5 percent (w/v) silicone polymer in 30% ethanol/70% THF; 1-5percent (w/v) silicone polymer in 30% reagent alcohol/70% THF; 1-2percent (w/v) polylactic acid in 30% methanol/70% THF; 1-2 percent (w/v)polylactic acid in 30% ethanol/70% THF; 1-2 percent (w/v) polylacticacid in 30% reagent alcohol/70% THF; 1-5 percent (w/v) silicone polymerin 100% methyl ethyl ketone; and 1-2 percent (w/v) polyurethane in 30%ethanol/70% THF. In general, such treatment solutions may comprisebetween 0.1 and 10 percent, and preferably between about 1 and 5percent, of one or more dissolved polymer. For specific examples, seeSections 11-12, below, and Section 10, which shows examples ofhydrophilic medical articles (e.g., latex urinary catheters) orhydrophobic medical articles (e.g., PTFE soft tissue hernia graftpatches) impregnated with triclosan and silver using a solution withoutpolymer.

[0041] The medical article, or a portion thereof, may be immersed in theimpregnating solution to swell, after which the article may be removedand dried at room temperature until all solvent has evaporated and thearticle is no longer swollen. Other methods may also be used, such thata substantially uniform coat of impregnating solution is applied. Duringthe swelling process, triclosan or other chlorinated phenol and silvercompound (and small amounts of polymer when present in the impregnatingsolution) may be distributed within the polymeric substrate of thearticle; during drying, the triclosan or other chlorinated phenol andsilver compound and biomedical polymer (where present) may migratesomewhat toward the surface of the article. In the case of PTFE devices,no apparent swelling occurs, however, the drugs are trapped in theinterstices of the substrate. After drying, the article may be rinsed ineither water or alcohol and wiped to remove any excess triclosan orother chlorinated phenol, silver compound, and/or polymer at thesurface. This may leave a sufficient amount of triclosan or otherchlorinated phenol and silver compound just below the surface of thearticle, thereby permitting sustained release over a prolonged period oftime.

4.6 TWO-STEP METHOD OF PREPARING ANTI-INFECTIVE MEDICAL ARTICLES

[0042] According to the two-step method of the invention, the one-stepmethod may be used to impregnate a medical article with triclosan and/orother chlorinated phenol and a silver compound, and then the medicalarticle may be dipped into a second treatment solution containingtriclosan and/or other chlorinated phenol and/or a silver compoundand/or one or more polymer, and dried. This method forms a coating onthe article and further controls the rate of release of triclosan orother chlorinated phenol and silver compound. For a non-limitingspecific example, see Section 7, below.

4.7 MEDICAL ARTICLES HAVING ANTI-ADHERENT PROPERTIES

[0043] It has been discovered that medical articles treated withmixtures of silver compounds and triclosan exhibit anti-adherentqualities and anti-microbial effectiveness, even in the absence ofchlorhexidine. While not being bound to any particular theory, it isbelieved that triclosan and silver compounds form a triclosan-silvercompound complex, such that impregnation of this triclosan-silvercompound complex into medical articles increases resistance to microbialadherence to the surfaces by rendering the surfaces smooth and shiny. Ithas further been discovered that the combination of silver compounds andother compositions, such as other chlorinated phenolic compounds,anti-inflammatory agents, hydrophilic and hydrophobic polymers andhydrogels each separately contribute to enhanced and prolongedantimicrobial efficacy of the antimicrobial agents. The synergisticcombinations of triclosan and silver compounds that are sparinglysoluble are especially suitable for forming a smooth surface and forproviding a sustained and prolonged release of anti-microbial agents.

[0044] In a specific example of a method of direct impregnation oftriclosan and a silver compound into a Dacron device, a treatmentsolution may be prepared including 1 to 6 percent triclosan and 0.1 to0.2 percent of a silver compound in a solvent mixture containing (v/v)10 percent ammonia, 10 percent alcohol and 80 percent THF. The devicemay be soaked for 1 to 10 minutes, dried and rinsed. In variations ofthis example, between about 1 and 10 percent of a hydrophilic polymer ora hydrophobic polymer may be included in the treatment solution.Suitable hydrophilic polymers include, but are not limited to, one ormore of polyurethane, polycaprolactone, and polyactic acid. Suitablehydrophobic polymers include, but are not limited to, silicone polymers.

4.8 MEDICAL ARTICLES COMPRISING TRICLOSAN, A SILVER COMPOUND, AND ANANTI-INFLAMMATORY AGENT

[0045] Anti-inflammatory agents such as salicylic acid,paraaminosalicylic acid, and acetylsalicylic acid were impregnated alongwith triclosan and a silver compound into medical devices to reduceinflammatory reaction around the wound at the insertion site and thusenhance wound healing. Surprisingly, it has been discovered thatincorporation of these anti-inflammatory agents along with the triclosanand a silver compound enhances the anti-microbial activity of thecomposition. Since the anti-inflammatory agents do not give zones ofinhibition when used alone, it appears that increased zone sizes,observed when the anti-inflammatory agents are added to the triclosanand silver compound combination, is not a result of an additive effectbut rather due to potentiation of the activity of the complex. Thus, thepresent invention provides for medical articles treated with treatmentsolutions comprising triclosan and/or other chlorinated phenol, a silvercompound, and an anti-inflammatory agent, such as salicylic acid or aderivative thereof. In further non-limiting embodiments, the treatmentsolution may also include an additional anti-infective agent such asthose set forth below, or chlorhexidine, or a chlorhexidine salt (at aconcentration of between about 0.1 and 5 percent).

4.9 ADDITION OF OTHER ANTI-INFECTIVE AGENTS

[0046] Because a major route of entry of pathogens during implantationof medical devices occurs at the insertion site and occurs at the timeof implantation, it is important to have an effective broad spectrumantimicrobial field around the device during implantation. In order toenhance the antimicrobial field around a device, antibiotic andanti-microbial agents may be added to medical articles comprisingtriclosan or other chlorinated phenol and a silver compound including,but not limited to, macrolides, aminoglycosides, penicillins,cephalosporins, quinolones, antifungal agents, chlorhexidine orbiguanides other than chlorhexidine, chlorinated phenols, sulfonamides,quarternary ammonium compounds, picloxydine, phenolic compounds (e.g.,orthophenylphenol), and polymeric quarternary ammonium compounds.Examples of specific agents which can be used include rifampicin,gramicidin, gentamycin, fusidic acid, miconazole, norfloxacin,polymixin, sulfamylon, furazolidine, alexidine, octenidinehydrochloride, cetrimide, polyhexamethylene biguanide, triclocarban,benzalkonium chloride, minocycline, iodine and iodine complexes such aspovidone iodine, pluroniciodine complex, benzoic acid, sorbic acid, andethylenediamine tetraacetic acid (EDTA).

[0047] These agents used in addition to the triclosan and/or otherchlorinated phenol and silver compound combination provide an effectivebroad spectrum anti-microbial field of activity initially, whichinactivates pathogens that otherwise can heavily contaminate the sterilefield during implantation. For a non-limiting specific example, seeSection 15.

[0048] The anti-adherent surface of these devices continues to preventadherence of microbes that may enter the device tract during andsubsequent to implantation. Once these additional agents are diffusedout of the devices, the anti-adherent surface continues to preventadherence of microbes which may contact the device surface throughhematogenous seeding or contaminated infusate. Further, without beingbound to any particular theory, it is believed that sustained andprolonged release of the anti-microbial agents occurs from the putativetriclosan-silver compound complex which provides a longer period ofprotection.

4.10 MEDICAL ARTICLES COMPRISING A HYDROGEL

[0049] According to the present invention, it has been determined thatthe use of hydrogel polymers increases the antimicrobial efficacy ofhydrophilic or hydrophobic matrix systems. In a particular embodiment,the present invention provides for a hydrophilic or hydrophobic medicalarticle which has been impregnated, coated or impregnated and coatedwith a treatment solution comprising (i) a hydrophilic or hydrophobicpolymer, (ii) one or more metal compounds comprising metal atoms or ionsor complexes comprising a metal atom or ion selected from the groupconsisting of silver, copper, zinc, calcium, aluminum and magnesium,(iii) triclosan or other chlorinated phenol, and (iv) a hydrogel. Suchmedical articles may further comprise, or the treatment solution maycomprise, a biguanide such as chlorhexidine or a chlorhexidine salt. Inother embodiments, the present invention provides for a metallic orceramic medical article coated with a treatment solution of (i) to (iv)as set out above. In a preferred embodiment, the hydrogel comprisespolyvinyl pyrrolidone (“PVP”). In another preferred embodiment, thehydrophobic polymer polyvinyl chloride (“PVC”) may be used to create ahydrophobic matrix into which PVP and antimicrobial agents may beimpregnated. Other useful hydrogels that may be used to promote enhancedantimicrobial efficacy include polyethylene oxide, pluronics, ethyl andmethyl cellulose, hydroxy ethyl and hydroxy methyl cellulose,incroquats, and polyhydroxyethyl methacrylate.

[0050] For a specific, non-limiting example, see Section 19, below.

[0051] The following working examples are intended to illustrate but notto limit the scope of the present invention.

5.0 EXAMPLE: TRICLOSAN IMPROVES THE SOLUBILITY OF SILVER COMPOUNDS

[0052] Table 1 illustrates the solubility of the silver salt, silvercarbonate, mixed at various molar ratios with ammonia, which is used ina treatment solution, in the absence and the presence of triclosan atvarious molar ratios. Table 2 illustrates the solubility of the silversalt, silver oxide, mixed at various molar ratios with ammonia in theabsence and presence of triclosan at various molar ratios. Thesolubility results demonstrated in Tables 1 and 2 indicate that silversalts are much more soluble in the presence of triclosan, which suggeststhat the silver compound and triclosan may form a complex.

[0053] When ammonia and silver carbonate were mixed at a high molarratio of 400 to 10, the silver salt remained insoluble in the solventsystem. In contrast, in the presence of 30 μmole of triclosan, the molarratio of ammonia to silver carbonate needed to solubilize was 50 to 10.Achieving a low molar ratio of ammonia to silver salt is preferredbecause the surface of devices impregnated with a solvent systemcontaining higher amounts of ammonia can be damaged, thereby enhancingthe likelihood of microbial adherence to the surface. In the case ofsilver oxide, only 10 μmole of ammonia was needed to solubilize morethan 90% of 10 μmole of silver oxide in the presence of 10 μmole oftriclosan. Further, only 20 μmole of triclosan was needed to completelysolubilize 10 μmole of silver oxide in the presence of only 10 μmole ofammonia. TABLE 1 Silver Carbonate Ammonia Triclosan (μmole) (μmole)(μmole) Solubility 10 100 0 Not Soluble 10 200 0 Not Soluble 10 300 0Not Soluble 10 400 0 Not Soluble 10 0 30 Not Soluble 10 50 10 PartiallySoluble 10 100 10 Partially Soluble 10 150 10 Soluble 10 75 20 PartiallySoluble 10 50 30 Soluble

[0054] TABLE 2 Silver oxide Ammonia (μmole) (μmole) TC (μmole)Solubility (μmole) 10 10 0 Not soluble 10 100 0 Soluble 10 10 10 >90%Soluble 10 10 20 Soluble

6.0 EXAMPLE: EVALUATION OF THE ANTI-MICROBIAL EFFICACY OFTRICLOSAN-SILVER COMPOUND COMBINATIONS IN BROTH CULTURES

[0055] The synergistic anti-microbial efficacy of the triclosan/silvercompound combination, triclosan/silver sulfadiazine, is illustrated bythe results shown in Table 3, and were determined by the followingprotocol. Drug solutions containing 10% ammonia were prepared inethanol, and 0.1 ml of each solution was added to 0.9 ml of bacterialculture (50% trypticase soy broth+50% Bovine Calf Serum containing 10⁸cfu S. aureus/ml). After 10 minutes, a 0.1 ml aliquot was removed andadded to 0.9 ml drug inactivating media (LTSB). 0.1 ml from this mediawas then added to another 0.9 ml of LTSB and 0.2 ml was subcultured ontrypticase soy agar plate and incubated at 37° C. for 24 hours. Thecolony counts were then determined. Control cultures contained similaramounts of ammonia and ethanol as in the test culture. TABLE 3 SolutionGrowth in Culture Triclosan (%) Silver Sulfadiazine (%) (cfu/ml) 0 0 2.1× 10⁷ 0.25 0 1.2 × 10⁷ 0.5 0   1 × 10⁷ 0 0.5   5 × 10⁶ 0 1.0 1.5 × 10⁶0.5 0.5 8.3 × 10⁵ 0.5 1.0 1.4 × 10⁴

[0056] These results show the synergistic activity of triclosan andsilver sulfadiazine. In the control, in the absence of either triclosanor silver sulfadiazine, there was growth in culture of the magnitude of2.1×10⁷ cfu/ml. Comparing the relative reduction of growth in culture bythe introduction of triclosan and silver sulfadiazine, the addition oftriclosan alone at 0.25 and 0.5 percent each resulted in a reduction ingrowth in culture of less than a power of 10 compared to the control.The addition of silver sulfadiazine alone at 0.5 and 1.0 percent eachresulted in a 1 log reduction of growth in culture compared to thecontrol.

[0057] Comparing the relative reduction of growth in culture by theintroduction of triclosan and silver sulfadiazine in combination, thecombination of 0.5 percent triclosan and 0.5 percent silver sulfadiazineresulted in a 2 log reduction in growth in culture compared with thecontrol. The combination of 0.5 percent triclosan and 1.0 percent silversulfadiazine resulted in a 3 log reduction in cell growth in culturecompared with the control. Moreover, the addition of 0.5 percent ofsilver sulfadiazine from 0.5 to 1.0 in the presence of 0.5 triclosanresulted in a 1 log reduction in growth in culture, whereas the increaseof 0.5 to 1.0 percent silver sulfadiazine in the absence of triclosandid not result in a significant decrease. The cell growth in culture inthe presence of 0.5 percent triclosan alone added to the cell growth inculture in the presence of 0.5 percent of silver sulfadiazine, thecombined presence of 0.5 triclosan and 1.0 silver sulfadiazine resultedin a 3 log reduction in growth in culture, and the increase of 0.5 to1.0 percent silver sulfadiazine compared to the growth in culture at 0.5percent triclosan results in a 1 log decrease.

[0058] The effects of triclosan and silver carbonate combinations on S.aureus growth in culture were also determined using the same protocol.The results are presented in Table 4. TABLE 4 Solution Growth in CultureTriclosan (%) Silver Carbonate (%) (cfu/ml) 0 0   5 × 10⁷ .25 0   2 ×10⁷ .5 0 1.2 × 10⁷ 0 .06   1 × 10⁵ 0 .125   2 × 10³ 0 .25   5 × 10² .5.06 3.2 × 10⁴ .5 .125 0 .5 .25 0

[0059] The results shown in Table 4 illustrate the synergistic activityof triclosan and silver carbonate. In the control, in the absence ofboth triclosan and silver carbonate the growth in cell culture was ofthe magnitude of 5×10⁷ cfu/ml. Combining 0.5 percent triclosan and 0.25percent silver carbonate resulted in a 7 log reduction in growth inculture. The addition of 0.5 percent triclosan alone resulted in a 0 logreduction, and the addition of 0.25 silver carbonate alone resulted in a5 log reduction. Therefore one would expect a 5 log reduction of growthin cell culture upon combining the two compositions. However, due to asynergistic activity present when triclosan is combined with silvercarbonate an additional 2 log reduction was observed.

[0060] Alone, 0.06 percent and 0.125 percent silver carbonate caused a 2log and a 4 log reduction in growth in culture, respectively, and 0.5percent triclosan alone caused a 0 log reduction. However, 0.06 percentand 0.125 percent silver carbonate each combined with 0.5 percenttriclosan resulted in, respectively, a 3 log reduction and a 7 logreduction of growth in culture.

7.0 EXAMPLE: ANTIMICROBIAL EFFICACY OF CATHETERS IMPREGNATED WITH (1)TRICLOSAN, SILVER SALTS AND VARIOUS ORGANIC ACIDS AND (2) TRICLOSAN,SILVER SALTS, AND CHLORHEXIDINE

[0061] Catheters impregnated with triclosan, silver compounds andvarious organic acids, with and without chlorhexidine, were evaluatedfor effectiveness and duration of antimicrobial efficacy. Treatmentsolutions comprising triclosan, a silver compound, and an organic acidor chlorhexidine as well as polyurethane polymers were prepared by firstdissolving the triclosan, silver compound, and acid or chlorhexidine inmethanol, dissolving the polymers in THF, and then mixing the methanolsolution with the THF solution in a 30% v/v methanol solution/70% v/vTHF solution solvent system. Polyurethane central venous cathetersegments were then dipped for one minute in the treatment solution, thenallowed to dry. The final concentrations (percentages based on w/v) ofactive agents and polymers in the treated catheters are set forth inTable 5.

[0062] In related experiments, polyurethane catheter segments weretreated by a two-step process. In the first step, catheters were dippedin a 70% v/v THF+30% v/v reagent alcohol treatment solution having finalconcentrations of 3% w/v 93A polyurethane and 1% 60D polyurethane,either with or without silver carbonate at a final concentration of 0.6%(the various components were dissolved in either THF or reagent alcoholbefore mixing the two to produce the treatment solution, as set forthabove). The catheters were allowed to dry. Then, in the second step, thecatheters were soaked for one minute in a 20% v/v THF+80% v/v methanolsolvent mixture containing either triclosan alone, triclosan and citricacid, or triclosan and chlorhexidine at concentrations set forth inTable 6.

[0063] The zones of inhibition were studied against S. epidermidis andP. aeruginosa over a two day period. The results, shown in Tables 5 and6, indicate that the combination of citric acid, triclosan and silvercompound (silver carbonate) resulted in superior antimicrobial activityagainst Pseudomonas aeruginosa, compared to other organic acids tested.TABLE 5 Zones of Inhibition (mm) S. epidermidis P. aeruginosa TreatmentSolution Day 1 Day 2 Day 1 Day 2 6% TC + 0.6% Ag₂CO₃ + 3% 20 18 9 0 93APU + 1% 60D PU 6% TC + 0.6% Ag₂CO₃ + 2% 20 18 11 0 salicylic acid + 3%93A PU + 1% 60D PU 6% TC + 0.6% Ag₂CO₃ + 2% 20 18 8 0 mandelic acid + 3%93A PU + 1% 60D PU 6% TC + 0.6% Ag₂CO₃ + 2% 20 18 8 0 deoxycholic acid +3% 93A PU + 1% 60D PU 6% TC + 0.6% Ag₂CO₃ + 2% 20 19 11 8 citric acid +3% 93A PU + 1% 60D PU 6% TC + 0.3% Ag₂CO₃ + 2% 21 20 13 12 CHX + 3% 93APU + 1% 60D PU

[0064] TABLE 6 Zones of Inhibition (mm) S. epi- P. dermidis aeruginosaFirst Step Treat- Second Step Day Day Day Day ment Solution TreatmentSolution 1 2 1 2 3% 93A PU + 1% 6% TC + 4% Citric Acid 20 18  0  0 60DPU 3% 93A PU + 1% 6% TC 20 18  9  0 60D PU + 0.6% Ag₂CO₃ 3% 93A PU + 1%6% TC + 4% Citric Acid 20 18 10  7 60D PU + 0.6% Ag₂CO₃ 3% 93A PU + 1%6% TC + 2% CHX 21 17 12 11 60D PU

8.0 EXAMPLE: METHODS OF PREVENTING ADHERENCE ON MEDICAL ARTICLES

[0065] The following techniques were used to impregnate 93A polyurethanecatheter segments with triclosan and various silver compounds. Theresulting surface characteristics, scored on a scale of 1 to 4, with 4being the most lubricious surface, are shown in Tables 7 and 8. Soakingtime varied from 15 seconds to 1 hour.

[0066] Method A: The outer surfaces of catheter segments wereimpregnated by dipping the segments in a treatment solution of 70% v/vTHF (containing 93A polyurethane and 60D polyurethane)+30% v/v (2:1reagent alcohol:ammonia containing triclosan and silver compound),having final concentrations of 3% w/v 93A polyurethane, 1% w/v 60Dpolyurethane, 0.3% w/v silver atom or ion, and 6% w/v triclosan.

[0067] Method B: Catheter segments had their ends sealed and were soakedfor 5 minutes in a treatment solution of 90% v/v (8:1 reagentalcohol/ammonia containing triclosan and silver compound)+10% THF,having final concentrations of 6% w/v triclosan and 0.3% silver (atom orion).

[0068] Method C: The ends of the catheter segments were sealed and thesegments were dipped in a treatment solution of 70% v/v THF (containing60D polyurethane)+30% v/v reagent alcohol having a final concentrationof 2% w/v 60D polyurethane. The catheter segments were then dried forone hour, and then were soaked for 5 minutes in a treatment solution of90% v/v (8:1 ethanol/ammonia containing triclosan and silvercompound)+10% THF, having final concentrations of 6% w/v triclosan and0.3% silver (the treatment solution used in Method B).

[0069] Method D: Catheter segments were dipped in a treatment solutionof 70% v/v THF (containing 93A polyurethane and 60D polyurethane)+30%v/v (2:1 reagent alcohol:ammonia containing a silver compound), havingfinal concentrations of 3% w/v 93A polyurethane, 1% w/v 60Dpolyurethane, and 0.3% w/v silver (atom or ion) (the treatment solutionused in Method A, but without the triclosan).

[0070] The surface characteristics of catheter segments treatedaccording to Methods A-D are shown in Table 7. TABLE 7 SurfaceCharacteristics Silver Salt A B C D 0 (only triclosan) 3 3 4 — Silvercarbonate 4 4 4 3 Silver deoxycholate 4 4 4 Rough Silver oxide 4 4 4 3Silver salicylate 4 4 4 2 Silver iodide 3 3 3 2 Silver sulfadiazine 3 22 2 Silver nitrate 4 4 4 4

[0071] Table 8 shows the results when the outer surfaces of cathetersegments were impregnated by dipping the catheters in a treatmentsolution of 70% v/v THF (containing 93A and 60D polyurethanes) and 30%v/v reagent alcohol (containing triclosan, an organic acid, and a silvercompound), having final concentrations of 3% w/v 93A polyurethane, 1%w/v 60D polyurethane, 0.3% w/v silver (atom or ion), 6% w/v triclosan,and 1% w/v organic acid. TABLE 8 Metal Salts and Acid in TC ComplexSurface Characteristics Silver carbonate + salicylic acid 3.5 Silvercarbonate + deoxycholic acid 3.5 Silver sulfadiazine + salicylic acid 3Silver sulfadiazine + deoxycholic acid 3 Silver carbonate + citric acid4 Silver sulfadiazine + citric acid 4 Silver sulfadiazine + palmiticacid 3.5 Silver sulfadiazine + propionic acid 3.5 Silver sulfadiazine +aspartic acid 3.5

9.0 EXAMPLE: ANTI-MICROBIAL POLYURETHANE CATHETERS PREPARED BY A SHORTERSOAKING TIME (15 SECONDS) AND HIGHER TRICLOSAN LEVELS (UP TO 15%) IN THEIMPREGNATION SOLUTION

[0072] A shorter soaking time is preferred in a drug/solvent systemsince it is less likely to negatively affect the physical integrity of apolymeric device, particularly a polyurethane catheter. In order toattain sufficient drug uptake using a shorter soaking time, it ispreferred to increase the amount of triclosan in solution to a range of10% to 15%. For example, polyurethane catheters were dipped in asolution containing 2% 60D polyurethane dissolved in 70% THF+30% reagentalcohol and allowed to dry for 1 hour. They were then soaked for 15seconds in a solution prepared by dissolving enough triclosan and AgNO₃in an 8:1 reagent alcohol/ammonia solution such that when a treatmentsolution was prepared containing 10% THF and 90% of the reagentalcohol/ammonia/triclosan/AgNO₃, the treatment solution contained 15%triclosan and 0.48% AgNO₃. As a comparison, catheters were prepared asabove with the following changes: the triclosan concentration wasreduced to 6% and the soaking time was increased to 1 minute. Theinitial drug levels, measured spectrophotometrically, and zones ofinhibition against S. epidermidis and P. aeruginosa were determined forcatheter samples of both groups and are shown in Table 9. TABLE 9 Zonesof Inhibition (mm) vs. S. vs. P. Treatment μg TC/cm epidermidisaeruginosa 15 sec × (15% TC + 436 11 4 0.48% AgNO₃) 1 mm × (6% TC + 41013 4 0.48% AgNO₃)

[0073] As illustrated in Table 9, both initial drug uptake and zone ofinhibition data indicate that a similar efficacy is obtainable using ahigher concentration of drug and a shorter soaking time. In addition, ashorter soaking time in a drug/solvent system is less likely tonegatively affect the physical integrity of the device.

10.0 EXAMPLE: IMPREGNATION OF TRICLOSAN-SILVER COMBINATION IN LATEXURINARY CATHETER AND PTFE SOFT TISSUE PATCHES (STP)

[0074] Segments of latex urinary catheters and PTFE soft tissue patches(STP) were impregnated by soaking these materials (or suctioning undervacuum in the case of PTFE STP) for 1 hour in a treatment solutionprepared by mixing 80% v/v THF and 10% v/v reagent alcohol/10% v/vammonia (containing triclosan and silver carbonate), having finalconcentrations of 1% w/v triclosan and 0.2% w/v silver carbonate. Theimpregnated materials were dried and then rinsed in water and driedagain. The antimicrobial properties of the material were then tested bymeasuring the zones of inhibition produced against S. aureus, P.aeruginosa, E. aerogenes and C. albicans after placing the treatedmaterial on a trypticase soy agar plate seeded with 0.3 ml of 10⁸ cfu/mlbacterial or yeast culture and incubating at 37° C. for 24 hours. Theresults are shown in Table 10. TABLE 10 Zones of inhibition (mm) UrinaryCatheter STP S. aureus 21 >30 P. aeruginosa 6 7 E. aerogenes 10 25 C.albicans 7 12

11.0 EXAMPLE: ANTIMICROBIAL EFFICACY OF SUBCUTANEOUS CUFFS CONTAININGFABRICS CONSISTING OF DACRON, ACRYLIC AND PTFE

[0075] The antimicrobial efficacy of subcutaneous cuff materialcontaining fabrics made of Dacron, Acrylic and PTFE were impregnatedwith a treatment solution prepared by mixing 10% v/v ammonia/10% v/vreagent alcohol (containing silver carbonate, triclosan andchlorhexidine) and 80% v/v THF (containing 93A and 60D polyurethanes),having final concentrations of 4% w/v 93A polyurethane, 1% w/v 60Dpolyurethane, 0.2% w/v silver carbonate, 0. 1% w/v triclosan and 0.5%w/v chlorhexidine, The resulting material was then dried for 24 hoursand the zones of inhibition against S. aureus and P. aeruginosa weredetermined. The zones of inhibition are shown in Table 11. TABLE 11 Zoneof Inhibition (mm) Cuff Material S. aureas P. aeruginosa Dacron 20 12Acrylic 19 12 PTFE 18 10

12.0 EXAMPLE: METHOD OF IMPREGNATION OF LEFT VENTRICULAR ASSIST DEVICE(LVAD) DRIVE LINES

[0076] Left ventricular assist device (LVAD) drive lines, which are madeof Dacron material and are attached to silicone tubing, were impregnatedwith a polymeric matrix containing triclosan and silver salts.

[0077] Dacron material was treated with one of two different treatmentsolutions as follows.

[0078] In a first case, Dacron material was uniformly spread with atreatment solution which was 10% v/v ammonia, 10% v/v reagent alcohol(containing silver carbonate and triclosan)+80% THF (containing 93A and60D polyurethanes), having final concentrations of 0.2% w/v silvercarbonate, 0.1% w/v triclosan, 4% w/v 93A polyurethane, and 1% w/v 60Dpolyurethane. As in previous examples, the silver carbonate andtriclosan were first dissolved in 1:1 ammonia/reagent alcohol, and thepolyurethanes were first dissolved in THF, and then the ammonia/reagentalcohol and THF were mixed to achieve the proper final ratios.

[0079] In a second case, Dacron material was uniformly spread with atreatment solution which was 10% v/v ammonia, 10% v/v reagent alcohol(containing silver carbonate, triclosan and chlorhexidine)+80% THF(containing 93A and 60D polyurethanes), having final concentrations of0.2% w/v silver carbonate, 0.5% w/v chlorhexidine, 0.1% w/v triclosan,4% w/v 93A polyurethane, and 1% w/v 60D polyurethane.

[0080] Dacron material having a polymer-drug film prepared as above wasthen attached to silicone tubing, thereby creating a drive line, anddried. This method is particularly important for devices in which tissueingrowth is intended to occur after implantation (e.g., cuffs).Antimicrobial activity was evaluated after 24 hours by measuring thezones of inhibition produced by placing 0.25 cm length of drive line ontrypticase soy agar seeded with 0.3 ml of 10 ⁸ cfu/ml bacteria andincubated at 37° C. for 24 hours. The zones of inhibition were measuredafter 24 hours, and the results are shown in Table 12. TABLE 12 Zones ofInhibition (mm) Drugs in Catheter S. aureus P. aeruginosa 0.2%Ag₂CO_(3,) 0.1% TC 16  6 0.2% Ag₂CO_(3,) 0.1% TC, 0.5% CHX 20 12

[0081] As shown in Table 12, drive line treated with polymer, silvercarbonate, and low levels of triclosan had antimicrobial activityagainst both S. aureus and P. aeruginosa. The antimicrobial effect wasimproved by the addition of chlorhexidine.

[0082] In related experiments, subcutaneous cuffs containing fragmentsconsisting of Dacron, acrylic or PTFE were impregnated by dipping in atreatment solution which is 10% v/v ammonia, 10% v/v reagent alcohol(containing silver carbonate, triclosan and chlorhexidine)+80% THF(containing 93A and 60D polyurethanes), having final concentrations of0.2% w/v silver carbonate, 0.5% w/v chlorhexidine, 0.1% w/v triclosan,4% w/v 93A polyurethane, and 1% w/v 60D polyurethane. The treatedmaterial was allowed to dry, and then tested for antimicrobial activityas set forth above. The results are shown in Table 13. TABLE 13 Zone ofInhibition (mm) Cuff Material S. aureas P. aeruginosa Dacron 20 12Acrylic 19 12 PTFE 18 10

13.0 EXAMPLE: BACTERIAL ADHERENCE ON TRICLOSAN-SILVER COMPOUNDIMPREGNATED CATHETERS POST IMPLANTATION IN RATS

[0083] The ability of catheters impregnated with triclosan and a silvercompound to resist bacterial adherence was tested by introducing andmaintaining treated catheters in vivo in rats, removing the catheters,exposing the catheters to bacterial cultures, and then measuring theamount of bacteria adhered to the extracted catheter segments.

[0084] The catheter segments were impregnated with triclosan and varioussilver compounds and/or chlorhexidine diacetate (CHA), using treatmentsolutions having the final concentrations of agents set forth in Table14, below. In each case, the amount of silver compound in the treatmentsolution contributed silver atom/ion at a concentration of 0.3% w/v. Thetreatment solutions comprised THF and reagent alcohol mixed solutions,where polyurethane components were dissolved in the THF and triclosanand silver compounds were dissolved in the reagent alcohol prior tomixing. The amount of THF/polyurethane was generally 70% (v/v). Theamount of reagent alcohol was 30% (v/v). Where indicated by an asteriskin Table 16, the solvent was simply reagent alcohol; otherwise, thesolvent system was reagent alcohol/ammonia in a 2:1 ratio (accountingfor 20% and 10%, respectively, on a volume to volume basis). Polymers inthe treatment solutions were initially dissolved in the THF componentand had final concentrations of 3% w/v 93A polyurethane and 1% w/v 60Dpolyurethane. Catheter segments were dipped in the treatment solution,and then dried for three days prior to use. Unimpregnated cathetersegments were used as controls.

[0085] Six 3 cm segments of catheters from each catheter group wereimplanted in a subcutaneous pocket on the dorsal side of laboratoryrats. After seven days the catheters were removed and rinsed twice insaline and processed as follows: Each group of catheter segments (6×3cm) were transferred to 18 ml of 10% BCS+90% TSB containing 3.0 ml of10⁷ cfu S. epidermidis/ml at 37° C. in a rotary shaker for 4 hours. Thenthe catheters were removed, blotted, rinsed twice in saline, blotted androlled over the surface of drug neutralizing agar plates (D/E plates)and incubated for 24 hrs at 37° C. The colony counts observed in Table14 were then determined for each catheter group. TABLE 14 Agents No. ofCatheter Segments in Treatment Catheter Segments Colonized (10²-10⁴Solution Not Colonized cfu/cm) 6% TC + 0.75% 0 6 AgSD 6% TC + 0.79% 0 6Ag paraamino salicylic acid 6% TC + 0.8% 0 6 Ag acetylsalicylic acid0.75% AgSD + 0 5 4% CHA* 6% TC + 0.6% 1 5 Ag salicylate 6% TC + 0.8% 1 5Ag laurate 6% TC + 1.5% 1 5 Ag deoxycholate 6% TC 1 4 6% TC + 0.32% 2 4Ag oxide 6% TC + 1% Ag 3 3 Paraamino benzoic acid 6% TC + 0.4% 4 2 AgCarbonate 6% TC + 0.48% 5 1 Ag Nitrate 6% TC + 0.4% 5 1 Ag Carbonate*control 1 0 4 control 2 1 5

[0086] As evidenced from the results of Table 14, the catheter groupscontaining triclosan-silver salt combinations were effective inpreventing bacterial adherence on catheters after being implanted forseven days in rats.

[0087] A further two sets of experiments were carried out to determinethe antimicrobial efficacy of catheters treated according to theinvention. In particular, one set of experiments involved an “initialinfection model” where the initial catheter wound site was inoculatedwith bacteria, and another set of experiments involved a “delayedinfection model” in which catheters implanted in rats for ten days wereremoved and exposed to bacterial cultures in vitro. In these two sets ofexperiments, the results of which are shown in Table 15, long term andshort term efficacy of treated catheters was evaluated and compared.

[0088] In experiments involving the “initial infection model”, thedorsal side of a rat was shaved and a 7 cm segment of catheter treatedwith the agents set forth in Table 15 (with both ends sealed withsilicone plugs) was implanted subcutaneously through a 0.5 cm incisionjust above the shoulder area. The catheter was kept in place, and thetract and insertion site were inoculated with 20 μl of bacterial culturehaving 10⁸ cfu of S. aureus per milliliter. The wound was then closedwith surgical clips. After ten days, the catheters were removed and swabcultures of the insertion site and tract were taken. Only the controlgroup had a positive swab culture. Bacterial adherence on the outersurface of the catheters was determined by sonicating the catheters indrug neutralizing media and then subculturing on a trypticase soy agarplate.

[0089] In experiments involving the “delayed infection model”, cathetersegments (3 cm each, with sealed ends, treated with the agents set forthin Table 15, in solvent systems that were 70% v/v THF and 30% v/vreagent alcohol and contained 3% w/v 93A and 1% w/v 60D polyurethanes)were implanted subcutaneously in rats (6 segments of catheters treatedwith the same agents per rat). After ten days in vivo, the catheterswere excised and rinsed twice with saline. Then each group of sixsegments was incubated in 18 ml of a log-phase culture of S. epidermidis(10⁷ cfu/ml of 10% bovine adult serum+90% TSB) in a rotary shaker forfour hours. The bacterial adherence was determined by sonicating thecatheters in drug neutralizing media and then subculturing on atrypticase soy agar plate.

[0090] Untreated catheters were implanted in rats of both models toserve as controls. TABLE 15 10 Days Initial Post Catheter GroupContamination* Contamination* Control 1 × 10³ >10⁵ 1.5% CHA + 0.75% AgSD10 5 × 10⁵ 2% CHA + 2% TC + 0.75%  0 1 × 10⁴ AgSD 6% TC + 0.36% AgNO₃ 3326 6% TC + 0.4% Ag₂CO₃ 90 1 × 10² 6% TC + 0.75% AgSD Not Done 1 × 10⁴

[0091] As shown in Table 15, triclosan/silver nitrate andtriclosan/silver carbonate treated catheter surfaces were found to bemore lubricious (as indicated by lower cfu associated with catheters 10days post-implantation), even though their antimicrobial activityappeared to be lower than that of chlorhexidine/silver sulfadiazine orchlorhexidine/triclosan/silver sulfadiazine treated catheters (asreflected by lower cfu in the initial contamination models). It appearsfrom these results that surface characteristics play an important rolein the prevention of delayed infection. Chlorhexidine containingcatheters were more effective in preventing initial infections whiletriclosan/silver compound catheters were more effective in preventinglater infections. The latter catheters showed significantly lowerbacterial adherence compared to control catheters when infectedinitially.

14.0 EXAMPLE: ABILITY OF TREATED PTFE PATCHES TO RESIST INFECTION IN ANANIMAL MODEL

[0092] The ability of PTFE soft tissue patches, treated withcombinations of triclosan and/or chlorhexidine and the silver salt,silver carbonate, to resist infection was tested as follows. Disks ofPTFE patches were impregnated with treatment solutions prepared bydissolving triclosan and/or chlorhexidine and silver carbonate in 1:1reagent alcohol/ammonium hydroxide, and then mixing with THF to producea 80% v/v THF, 10% reagent alcohol, 10% v/v ammonium hydroxide solutionhaving triclosan, chlorhexidine, and silver carbonate finalconcentrations as specified in Table 16 below. The patch material wassoaked in treatment solution for 1 hour under a vacuum. The patches wereimplanted subcutaneously in a pocket in the abdominal area of rats andinfected with 10 μl of 10⁸ CFU S. aureus. After 7 days, they wereremoved and bacterial adherence was determined by sonicating thecatheters in drug neutralizing media and then subculturing on atrypticase soy agar plate. The efficacy of patches in resistinginfection due to contamination at the time of implantation isillustrated by the bacterial adherence data provided in Table 16. TABLE16 Bacterial Adherence Impregnation Solution CFU/DISK 0.25% TC + 0.2%Ag₂CO₃ + 0.5 CHX  4 1.0% TC + 0.2% Ag₂CO₃  1 0.5% CHX + 0.2% Ag₂CO₃ 150.5% TC + 0.25% CHA + 0.25% CHX 15 Unimpregnated 7.6 × 10³

[0093] As shown in Table 16, all of the above groups with and withoutchlorhexidine were observed to be similarly efficacious relative to thecontrol, unimpregnated group.

15.0 EXAMPLE: ENHANCEMENT OF THE ANTI-MICROBIAL ACTIVITY OF DEVICESCONTAINING SILVER AND TRICLOSAN USING OTHER SOLUBLE ANTI-INFECTIVEAGENTS

[0094] Polyurethane catheter segments were impregnated by dipping in atreatment solution prepared by mixing 10% v/v ammonia/20% v/v reagentalcohol (containing triclosan, silver carbonate, and, except for thecontrol, an additional antibiotic) with 70% v/v THF (containing 93A and60D polyurethanes), having final concentrations of 3% w/v 93Apolyurethane, 1% w/v 60D polyurethane, 6% w/v triclosan, 0.4% w/v Ag₂CO₃and 0.5% of the antibiotics set forth in Table 17, below. The treatedcatheter segments were then dried for 24 hours and evaluated forantimicrobial activity by determining the zones of inhibition created incultures of various microbes. The antimicrobial properties of thematerial were then tested by measuring the zones of inhibition producedagainst S. aureus, P. aeruginosa, E. aerogenes and C. albicans afterplacing the treated material on a trypticase soy agar plate seeded with0.3 ml of 10⁸ cfu/ml bacterial/yeast culture and incubating at 37° C.for 24 hours.

[0095] Table 17 shows the enhanced effective broad spectrumanti-microbial field around a catheter produced by the addition ofsoluble anti-infective agents. Using antibiotics along with thetriclosan-silver salt combination may reduce the risk of development ofantibiotic resistant microbes. TABLE 17 Agents in Treatment Zones ofInhibition (mm) Solution S. aureus P. aeruginosa E. aerogens C.albincans 6% TC + 0.4% 14  6  7  7 Ag₂CO₃ + 0.5% Gram- icidin 6% TC +0.4% 17 16 15  7 Ag₂CO₃ + 0.5% Poly- mixin 6% TC + 0.4% 19 18 18 10Ag₂CO₃ + 0.5% Nor- floxacin 6% TC + 0.4% 12 12 13  9 Ag₂CO₃ + 0.5% Sulf-amylon 6% TC + 0.4% 21  5  5  0 Ag₂CO₃ + 0.5% Rif- ampincin 6% TC + 0.4%13  6  6  5 Ag₂CO₃ + NO ANTI- BIOTIC (CONTROL)

16.0 EXAMPLE: ANTIMICROBIAL ACTIVITY OF VARIOUS TRICLOSAN-SILVERCOMPOUND COMBINATIONS

[0096] Polyurethane catheter segments were treated by dipping in atreatment solution having final concentrations of triclosan and/orsilver compound as set forth in Table 18, below, where the solventsystem was 70% v/v THF and 30% v/v reagent alcohol and contained 3% w/v93A and 1% w/v 60D polyurethanes. Six catheter segments from each groupwere placed vertically on a trypticase soy agar plate seeded with 0.3 mlof 10⁸ cfu/ml bacterial/yeast culture and incubated at 37° C. for 24hours. The results are shown in Table 18. TABLE 18 Drug in Zones ofInhibtion (mm) Impregnation Enterobacter Candida Solution S. aureus P.aeruginosa aerogenes albicans 6% TC 15 0 6 0 1% AgSD 8 5 0 0 0.5% Ag₂CO₃8 7 0 6 0.6% Ag- 9 6.5 0 7.3 Salicylate 0.32% Ag 9 7 0 11 Oxide 1.5% Ag1 4 0 5 Deoxycholate 6% TC + 1% 17 6 5 5 AgSD 6% TC + 0.5% 22 9 6 7Ag₂CO₃ 6% TC + 0.6% 20 10 7 11 Ag Salicylate 6% TC + 0.32% 22 10 6 15 AgOxide 6% TC + 1.5% 17 7 5 10 Ag Deoxycholate 2% TC + 1% 17 11 12 13AgSD + 2% CHX 6% TC + 0.7% 17 7 6 5 Ag Parammino Benzoate acid 6% TC +0.79% 19 7 6 4 Ag Paraamino Salicylate 6% TC + 0.8% 19 8 7 9 Ag Acetyl-Salicylate 0.7% Ag 3.5 4.0 0 0 Paraamino Benzoate 0.79% Ag 5.5 7.5 3.3 0Paraamino Salicylate 0.8% Ag 7.0 8.0 4.7 0 Acetyl Salicylate

[0097] It is noted that the combination of triclosan with either silverparaaminobenzoate, silver paraaminosalicylate, or silveracetylsalicylate resulted in unexpected efficacy against C. albicans ascompared with each of the agents tested alone. Also illustrated by Table18 is the synergistic effect achieved by the presence of triclosan incombination with silver salts.

17.0 EXAMPLE: IMPREGNATION OF ANTI-INFLAMMATORY AGENTS ALONG WITHTRICLOSAN AND SILVER SALTS

[0098] The following experiments demonstrated that the addition of theanti-inflammatory agent salicylic acid and its derivatives tocombinations of triclosan and silver compounds improved antimicrobialactivity.

[0099] LVAD drive lines made of Dacron were impregnated with triclosan,silver sulfadiazine and chlorhexidine, with or without salicylic acid,as follows. One set of pieces of Dacron were uniformly spread with atreatment solution prepared by mixing 30% v/v reagent alcohol(containing triclosan (TC), silver sulfadiazine (AgSD), andchlorhexidine (CHX)) and 70% v/v THF (containing 93A and 60Dpolyurethanes), having final concentrations of 0.1% w/v triclosan, 0.2%w/v silver sulfadiazine, 0.5% w/v chlorhexidine, 4% w/v 93Apolyurethane, and 1% w/v 60D polyurethane. Another set of Dacron pieceswere uniformly spread with a second treatment solution having the samecomponents, but also having a final concentration of 0.5% w/v salicylicacid (the salicylic acid being initially dissolved in the reagentalcohol component). As a control, one set of Dacron pieces was treatedwith a third treatment solution containing salicylic acid and polymerbut lacking triclosan, silver sulfadiazine, and chlorhexidine. TheDacron pieces were dried for 24 hours prior to antimicrobial testing.

[0100] In an analogous set of experiments, polyurethane catheters wereimpregnated with triclosan and silver carbonate, with or withoutsalicylic acid or one of its derivatives. One set of polyurethanecatheter segments were therefor dipped in a treatment solution preparedby mixing 20% v/v reagent alcohol/10% v/v ammonia (containing triclosanand silver carbonate ) and 70% v/v THF (containing 93A and 60Dpolyurethanes), having final concentrations of 6% w/v triclosan, 0.4%w/v silver carbonate, 3% w/v 93A polyurethane and 1% w/v 60Dpolyurethane. Three other sets of catheter segments were treated withthe same solution further having a final concentration of 0.5% w/vsalicylic acid, 0.5% w/v acetylsalicylic acid, or 0.5% w/vparaaminosalicylic acid, respectively (the salicylic acid or derivativethereof being first dissolved in the ethanol/ammonia solution). Ascontrols, another three sets of catheters were impregnated usingtreatment solutions as above, containing either 0.5% w/v salicylic acid,0.5% w/v acetylsalicylic acid, or 0.5% w/v paraaminosalicylic acid andpolymer, but lacking triclosan or silver carbonate. The treatedcatheters were dried for 24 hours prior to antimicrobial testing.

[0101] Antimicrobial testing was performed by placing the Dacron driveline or catheter segment on trypticase soy agar seeded with 5×10⁸ cfu ofPseudomonas aeruginosa. The zones of inhibition were measured afterinclubation of the plates at 37° C. for 24 hours. The results, presentedin Table 19, illustrate that both hydrophilic (polyurethane) andhydrophobic (Dacron) medical devices can be rendered infection resistantand that anti-inflammatory agents such as salicylates enhanceantimicrobial activity. TABLE 19 Zones of Inhibition (mm) against P.aeruginosa Agents in LVAD Polyurethane Treatment Solution DriveLineCatheters 0.1% TC + 0.2% AgSD + 0.5% CHX 12 — 0.1% TC + 0.2% AgSD + 0.5%CHX + 15 — 0.5% Salicylic acid 0.5% Salicylic Acid  0 — 6% TC + 0.4%Ag₂CO₃ —  7 6% TC + 0.4% Ag₂CO_(3 + 0.5%) — 11 Salicylic Acid 6% TC +0.4% Ag₂CO₃ + 0.5% — 11 Acetylsalicylic Acid 6% TC + 0.4% Ag₂CO₃ + 0.5%— 11 Paraaminosalicylic Acid 0.5% Salicyic Acid —  0 0.5%Acetylsalicylic Acid —  0 0.5% Paraaminosalicylic Acid —  0

18.0 EXAMPLE: ANTI-MICROBIAL EFFICACY OF COMBINATIONS OF SILVER SALTSAND CHLORINATED PHENOLIC COMPOUNDS

[0102] Silver compounds, in particular silver salts and various phenoliccompounds were combined to study prolonged anti-microbial efficacy ofthe various compositions. Catheter segments for study were prepared bytreating a polyurethane catheter segment in a treatment solution having70% v/v THF and 30% v/v reagent alcohol and concentrations of 3% w/v 93Apolyurethane and 1% w/v 60D polyurethane, having final concentrations ofagents set forth in Table 20. Then segments were placed on petri dishesseeded with Pseudomonas aeruginosa. Table 3 illustrates the zones ofinhibition of Pseudomonas aeruginosa over a three day period of Ag₂CO₃and Ag₂CO₃ in combination with three phenolic compositions, (1)parachlorometaxylenol (PCMX), (2) o-phenyl phenol and (3) p-tertiaryamyl phenol, and compared their respective efficacy to triclosan andAg₂CO₃. As shown in Table 20 it appears that a synergistic effect occurswhen chlorinated phenols are combined with silver salt exhibitingprolonged anti-microbial activity. TABLE 20 Zones of Inhibiton (mm) DAYDrugs in Catheter 1 2 3 6% triclosan + 0.6% Ag₂CO₃ 11 10 6 6% PCMX +0.6% Ag₂CO₃ 12 10 7 6% 0-phenyl phenol + 0.6% Ag₂CO₃ 10  0 0 6%p-tertiary amyl phenol + 0.6% Ag₂CO₃ 10  0 0 0.6% Ag₂CO₃ 10  0 0

19.0 ANTIMICROBIAL EFFICACY OF HYDROPHILIC OR HYDROPHOBIC MATRIX SYSTEMSBY ADDITION OF HYDROGEL POLYMER

[0103] We tested the effect on antimicrobial activity of adding ahydrogel polymer such as polyvinyl pyrrolidone (PVP) to treatmentsolutions containing triclosan, silver compound, and polyurethanes, andthen using such solutions to treat medical devices. Polyurethanecatheter segments were dipped in one of the following two treatmentsolutions:

[0104] (i) a treatment solution prepared by mixing 30% v/v reagentalcohol (containing triclosan and silver carbonate) with 70% v/v THF(containing 93A and 60D polyurethanes), having final concentrations of6% w/v triclosan, 0.4% w/v silver carbonate, 3% w/v 93A polyurethane,and 1% w/v 60D polyurethane; or

[0105] (ii) a treatment solution prepared by mixing 30% v/v reagentalcohol (containing triclosan and silver carbonate) with 70% v/v THF(containing 60D polyurethane and PVP), having final concentrations of 6%w/v triclosan, 0.4% w/v silver carbonate, 3% w/v 60D polyurethane, and2% w/v PVP.

[0106] The treated catheter segments were then dried for 24 hours andthen tested for antimicrobial activity by measuring the zones ofinhibition The antimicrobial properties of the material were then testedby measuring the zones of inhibition produced against S. epidermidis andP. aeruginosa after placing the treated material on a trypticase soyagar plate seeded with 0.3 ml of 10⁸ cfu/ml bacterial culture andincubating at 37° C. for 24 hours.. In addition, the amount of triclosanpresent per centimeter of catheter was determinedspectrophotometrically. The results are shown in Table 21. TABLE 21Zones of Inhibition (mm) Compounds in vs. vs. Treatment Solution μgTC/cm S. epidermidis P. aeruginosa 6% TC + 0.4% Ag₂CO₃ + 425 11 6.5 3%93A PU + 1% 60D PU 6% TC + 0.4% Ag₂CO₃ + 397 18 10 3% 60D PU + 2% PVP

[0107] In other experiments, the effect of PVP incorporated into ahydrophobic article, i.e., Dacron material for LVAD drive lines, wasdetermined. In particular, pieces of Dacron were uniformly spread withone of the two following treatment solutions:

[0108] (iii) a treatment solution prepared by mixing 10% v/v reagentalcohol (containing triclosan, chlorhexidine diacetate (CHA),chlorhexidine free base (CHX) and silver sulfadiazine) with 90% v/v THF(containing 93A and 60D polyurethanes), having final concentrations of0.2% w/v triclosan, 0.3% w/v chlorhexidine diacetate, 0.2% w/vchlorhexidine free base, 0.2% w/v silver sulfadiazine, 4% w/v 93Apolyurethane, and 1% w/v 60D polyurethane, or

[0109] (iv) a treatment solution prepared by mixing 10% v/v reagentalcohol (containing triclosan, chlorhexidine diacetate (CHA),chlorhexidine free base (CHX) and silver sulfadiazine) with 90% v/v THF(containing 93A and 60D polyurethanes and PVP and polyvinylchloride(“PVC”)), having final concentrations of 0.2% w/v triclosan, 0.3% w/vchlorhexidine diacetate, 0.2% w/v chlorhexidine free base, 0.2% w/vsilver sulfadiazine, 4% w/v 93A polyurethane, 1% w/v 60D polyurethane,2% w/v PVP and 4% w/v PVC.

[0110] The treated Dacron was allowed to dry for 24 hours and thenattached to the outer surface of silicon tubing using a silicon adhesiveto produce a drive line. The resulting drive lines were then tested forantimicrobial activity by measuring the zones of inhibition producedagainst S. epidermidis, P. aeruginosa, and C. albicans after placing thetreated material on a trypticase soy agar plate seeded with 0.3 ml of10⁸ cfu/ml bacterial or yeast culture and incubating at 37° C. for 24hours. In addition, the amounts of triclosan and chlorhexidine presentper centimeter of Dacron were determined spectrophotometrically. Theresults are shown in Table 22. TABLE 22 Zones of Inhibition (mm) Groupμg TC/cm μg CHX/cm v. S. epidermidis v. P. aeruginosa v. C. albicans LXI387 662 17 11.5 14 LXII 420 480 22 15 16

[0111] As illustrated in Tables 21 and 22, the use of a hydrogel such asPVP in a hydrophilic (e.g., polyurethane) or hydrophobic (e.g., PVC)matrix allows better drug release as evidenced by greater zones ofinhibition.

[0112] Various publications are cited herein, which are herebyincorporated by reference in their entireties.

We claim:
 1. An anti-infective medical article prepared by exposing apolymer-containing medical article, for an effective period of time, toa treatment solution comprising between about 0.3 and 1.5 percent of asilver salt and between about 0.1 and 20 percent triclosan, where thetreatment solution and the medical article do not contain chlorhexidineor a chlorhexidine salt.
 2. The anti-infective medical article of claim1 , where the treatment solution further comprises an organic acid at aconcentration of between about 0.1 and 5 percent.
 3. The anti-infectivemedical article of claim 2 , where the organic acid is citric acid. 4.The anti-infective medical article of claim 1 , where the treatmentsolution further comprises an anti-inflammatory agent, at aconcentration of between about 1 and 5 percent.
 5. The anti-infectivemedical article of claim 4 , where the anti-inflammatory agent issalicylic acid or a derivative thereof.
 6. The anti-infective medicalarticle of claim 1 , where the treatment solution further comprises anadditional antimicrobial agent.
 7. The anti-infective medical article ofclaim 6 , where the additional antimicrobial agent is selected from thegroup consisting of gramicidin, polymixin, norfloxacin, sulfamylon,polyhexamethylene biguanide, alexidine, minocycline, iodine,benzalkonium chloride and rifampicin.
 8. The anti-infective medicalarticle of claim 1 , where the treatment solution further comprisesbetween about 1 and 5 percent of one or more hydrophilic or hydrophobicpolymer.
 9. The anti-infective medical article of claim 1 which is apolytetrafluoroethylene patch.
 10. A polymer-containing vascularcatheter comprising between about 100 and 600 micrograms of triclosan inreleasable form per centimeter and between about 25 and 100 microgramsof silver atom or ion in releasable form per centimeter, where thecatheter does not contain chlorhexidine or a chlorhexidine salt.
 11. Amethod of preparing an anti-infective medical article comprisingexposing a polymer-containing medical article, for an effective periodof time, to a treatment solution comprising between about 0.3 and 1.5percent of a silver salt and between about 0.1 and 20 percent triclosan,where the treatment solution and the medical article do not containchlorhexidine or a chlorhexidine salt.
 12. The method of claim 11 ,where the treatment solution further comprises an organic acid at aconcentration of between about 0.1 and 5 percent.
 13. The method ofclaim 12 , where the organic acid is citric acid.
 14. The method ofclaim 11 , where the treatment solution further comprises ananti-inflammatory agent, at a concentration of between about 1 and 5percent.
 15. The method of claim 14 , where the anti-inflammatory agentis salicylic acid or a derivative thereof.
 16. The method of claim 11 ,where the treatment solution further comprises an additionalantimicrobial agent.
 17. The method of claim 14 , where the additionalantimicrobial agent is selected from the group consisting of gramiciain,polymixin, norfloxacin, sulfamylon, polyhexamethylene biguanide,alexidine, minocycline, iodine, benzalkonium chloride and rifampicin.18. The method of claim 11 , where the treatment solution furthercomprises between about 1 and 5 percent of one or more hydrophilic orhydrophobic polymer.
 19. The method of claim 11 , where thepolymer-containing medical article is a polytetrafluoroethylene patch.20. An anti-infective medical article prepared by exposing apolymer-containing medical article, for an effective period of time, toa treatment solution comprising between about 0.3 and 1.5 percent of asilver compound and between about 0.1 and 20 percent of a chlorinatedphenol, where the chlorinated phenol is not triclosan.
 21. Theanti-infective medical article of claim 20 , where the chlorinatedphenol is parachlorometaxylenol.
 22. An anti-infective medical articleprepared by exposing a polymer-containing medical article, for aneffective period of time, to a treatment solution comprising betweenabout 0.1 and 5 percent of a metal compound, between about 0.1 and 20percent triclosan, and between about 0.5 and 10 percent of a hydrogel.23. The anti-infective medical article of claim 22 , where the metalcompound is a silver compound.
 24. The anti-infective medical article ofclaim 22 , where the hydrogel comprises polyvinyl pyrrolidone.
 25. Ananti-infective medical article prepared by exposing a polymer-containingmedical article, for an effective period of time, to a treatmentsolution comprising between about 0.1 and 5 percent of a silvercompound, between about 0.1 and 20 percent of triclosan, and betweenabout 1 and 5 percent of an anti-inflammatory agent.
 26. Theanti-infective medical article of claim 25 , where the anti-inflammatoryagent is salicylic acid or a derivative thereof.
 27. The anti-infectivemedical article of claim 25 , where the treatment solution furthercomprises an additional antimicrobial agent.
 28. The anti-infectivemedical article of claim 27 , where the additional antimicrobial agentis selected from the group consisting of chlorhexidine, a chlorhexidinesalt, gramicidin, polymixin, norfloxacin, sulfamylon, polyhexamethylenebiguanide, alexidine, minocycline, iodine benzalkonium chloride andrifampicin.
 29. The anti-infective medical article of claim 25 which isa polytetrafluoroethylene graft.
 30. A method of preparing ananti-infective medical article, comprising exposing a polymer-containingmedical article, for an effective period of time, to a treatmentsolution comprising between about 0.3 and 1.5 percent of a silvercompound and between about 0.1 and 20 percent of a chlorinated phenol,where the chlorinated phenol is not triclosan.
 31. The method of claim30 , where the chlorinated phenol is parachlorometaxylenol.
 32. A methodof preparing an anti-infective medical article comprising exposing apolymer-containing medical article, for an effective period of time, toa treatment solution comprising between about 0.1 and 5 percent of ametal compound, between about 0.1 and 20 percent triclosan, and betweenabout 0.5 and 10 percent of a hydrogel.
 33. The method of claim 32 ,where the metal compound is a silver compound.
 34. The method of claim32 , where the hydrogel comprises polyvinylpyrrolidone.
 35. A method ofpreparing an anti-infective medical article comprising exposing apolymer-containing medical article, for an effective period of time, toa treatment solution comprising between about 0.1 and 5 percent of asilver compound, between about 0.1 and 20 percent of triclosan, andbetween about 1 and 5 percent of an anti-inflammatory agent.
 36. Themethod of claim 35 , where the anti-inflammatory agent is salicylic acidor a derivative thereof.
 37. The method of claim 35 , where thetreatment solution further comprises an additional antimicrobial agent.38. The method of claim 34 , where the additional antimicrobial agent isselected from the group consisting of chlorhexidine, a chlorhexidinesalt, gramicidin, polymixin, norfloxacin, sulfamylon, polyhexamethylenebiguanide, alexidine, minocycline, iodine benzalkonium chloride andrifampicin.